Abstract 5917: A novel lipid nanoparticle (NBF-006) encapsulating glutathione S-transferase P (GSTP) siRNA for the treatment of KRAS-driven non-small cell lung cancer

Abstract

Abstract Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers and KRAS mutation occurs in 25-30% of NSCLC. Therapeutics directly targeting KRAS mutant proteins are currently not available. We developed a novel siRNA therapeutic against Glutathione S-Transferase P (GSTP), a gene target that is highly expressed in KRAS mutant NSCLC and is also involved in modulating RAS signaling pathway proteins. GSTP has been known as a Phase II detoxification enzyme and a modulator of MAP kinase-related cell-signaling pathways. Therefore, developing a GSTP inhibiting siRNA may be an effective therapeutic approach to treat KRAS mutant NSCLC. The lead drug product candidate (NBF-006) is a proprietary siRNA-based lipid nanoparticle (LNP) with a size of less than 70 nm, comprising GSTP siRNA (NDT-05-1040) and a novel ionizable, non-immunogenic, biodegradable lipid developed to target tumors in the lung. Our studies evaluated biodistribution and in vivo antitumor activities of NBF-006 in KRAS mutant NSCLC xenograft models. NBF-006 delivered siRNA molecules favorably to the lungs and tumor as compared to other tissues, with 70-80% of tumor cells showing siRNA uptake. Significant tumor growth inhibition (P <0.05) was observed in xenograft models derived from A549 (KRASMUT/TP53WT) and H23 (KRASMUT/TP53MUT) NSCLC cells, with notable tumor regression in A549 tumors and highly significant tumor regression in the H23 tumors following once-a-week administration. In the bioluminescent orthotopic lung tumor model, the average luminescent signal response in the NBF-006 treatment group was markedly lower than the vehicle control group (14.3 vs. 69.6 million photon/second, P <0.05). Additionally, in a surgically implanted orthotopic lung tumor model, the survival rate of the NBF-006 treatment group was significantly prolonged (P <0.005) at a 4 mg/kg dose compared to the vehicle control group. Finally, NBF-006 treatment was well tolerated in the preclinical efficacy models. In summary, we conclude that NBF-006 is selectively delivered to lung tumor tissue and its considerable uptake by tumor cells results in significant tumor growth inhibition and overall survival benefit as demonstrated in our preclinical models of KRAS mutant NSCLC. *These authors contributed equally. Citation Format: Zhihong O'Brien*, Li Wang*, Bharat Majeti*, Jeanpierre Clamme, Robiel Baclig, James Chu, Steven Fong, Jens Harborth, Jose Ibarra, Haiqing Yin, Jing Yu, Clayton Zhang, Roger Adami, Sonya Zabludoff, Wenbin Ying. A novel lipid nanoparticle (NBF-006) encapsulating glutathione S-transferase P (GSTP) siRNA for the treatment of KRAS-driven non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5917.